SEPT5 confers radioresistance by suppressing GSDME-dependent pyroptosis and antitumor immunity in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) remains a major cause of cancer mortality worldwide, and radioresistance significantly compromises the efficacy of radiotherapy. However, the precise molecular determinants governing NSCLC radiosensitivity remain incompletely defined. Here, we identify SEPT5 as a key regulator of radioresistance, which is aberrantly upregulated in radioresistant NSCLC tissues and cell lines. Mechanistically, reduced expression of the deSUMOylase SENP3 leads to enhanced SUMO3 conjugation of SEPT5 at Lysine 296, thereby protecting it from ubiquitin-proteasome degradation. Accumulated SEPT5 then exerts a dual regulatory effect on the E3 ubiquitin ligase UBE3B. SEPT5 facilitates PCBP3 binding to the 3'-UTR of UBE3B mRNA, stabilizing the transcript and upregulating UBE3B expression. Concurrently, SEPT5 directly recruits UBE3B to promote K48-linked ubiquitination of GSDME at lysines 39 and 120, triggering its proteasomal degradation and suppressing irradiation-induced pyroptosis. Functionally, SEPT5 depletion restores GSDME-dependent pyroptosis and sensitizes NSCLC cells to radiotherapy in vitro and in vivo. More significantly, targeting SEPT5 potentiates the cytotoxic function of tumor-infiltrating CD8+ T cells and cooperatively represses NSCLC progression when combined with anti-PD-1. Collectively, these findings define an integrated mechanism in which SUMOylation-dependent stabilization of SEPT5 and UBE3B-mediated GSDME degradation converge to suppress pyroptosis and attenuate antitumor immunity, positioning the SEPT5 regulatory axis as a potential therapeutic vulnerability to overcome radioresistance and enhance the efficacy of immunotherapy.